Astragaloside IV Suppresses Hepatic Proliferation in Regenerating Rat Liver after 70% Partial Hepatectomy via Down-Regulation of Cell Cycle Pathway and DNA Replication.

Astragaloside IV (AS-IV) is one of the major bio-active ingredients of huang qi which is the dried root of Astragalus membranaceus (a traditional Chinese medicinal plant). The pharmacological effects of AS-IV, including anti-oxidative, anti-cancer, and anti-diabetic effects have been actively studied, however, the effects of AS-IV on liver regeneration have not yet been fully described. Thus, the aim of this study was to explore the effects of AS-IV on regenerating liver after 70% partial hepatectomy (PHx) in rats. Differentially expressed mRNAs, proliferative marker and growth factors were analyzed. AS-IV (10 mg/kg) was administrated orally 2 h before surgery. We found 20 core genes showed effects of AS-IV, many of which were involved with functions related to DNA replication during cell division. AS-IV down-regulates MAPK signaling, PI3/Akt signaling, and cell cycle pathway. Hepatocyte growth factor (HGF) and cyclin D1 expression were also decreased by AS-IV administration. Transforming growth factor ß1 (TGFß1, growth regulation signal) was slightly increased. In short, AS-IV down-regulated proliferative signals and genes related to DNA replication. In conclusion, AS-IV showed anti-proliferative activity in regenerating liver tissue after 70% PHx.

SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside.

Liver regeneration is critical to survival after traumatic injuries, exposure to hepatotoxins, or surgical interventions, yet the underlying signaling and metabolic pathways remain unclear. In this study, we show that hepatocyte-specific loss of the mitochondrial deacetylase SIRT3 drastically impairs regeneration and worsens mitochondrial function after partial hepatectomy. Sirtuins, including SIRT3, require NAD as a cosubstrate. We previously showed that the NAD precursor nicotinamide riboside (NR) promotes liver regeneration, but whether this involves sirtuins has not been tested. Here, we show that despite their NAD dependence and critical roles in regeneration, neither SIRT3 nor its nuclear counterpart SIRT1 is required for NR to enhance liver regeneration. NR improves mitochondrial respiration in regenerating WT or mutant livers and rapidly increases oxygen consumption and glucose output in cultured hepatocytes. Our data support a direct enhancement of mitochondrial redox metabolism as the mechanism mediating improved liver regeneration after NAD supplementation and exclude signaling via SIRT1 and SIRT3. Therefore, we provide the first evidence to our knowledge for an essential role for a mitochondrial sirtuin during liver regeneration and insight into the beneficial effects of NR.

Therapeutic potential of quinoa seed extract as regenerative and hepatoprotective agent in induced liver injury wistar rat model.

The liver is a fundamental metabolic organ that performs many essential functions including the detoxification of toxic substances present in the body. Exposure to various toxicants leads the liver towards hepatic injury. This study was planned to estimate the hepatoprotective and regenerative efficacy of Quinoa seeds (Chenopodium quinoa) extract against carbon tetrachloride (CCl4) induced liver damage. At a dose of 1ml/kg (153.8mg/kg) body weight carbon tetrachloride (CCl4) was used intraperitoneally to induce hepatic injury in Wistar rats. Silymarin (30mg/kg body weight, p.o.), an antioxidant was used as a reference standard drug. Subsequently, ethanolic extract of Quinoa seeds (QEE) was administered at 400 and 600mg/kg body weight through oral gavage. Various biochemical and regenerative biomarkers were assessed to evaluate the potential efficacy of QEE in liver tissue regeneration. Results revealed that QEE administration significantly reduced the CCl4-induced raised quantities of alanine transaminase (ALT), aspartate transaminase (AST), and total oxidative stress (TOS) while, significantly improved the level of triiodothyronine (T3), thyroxine (T4), albumin and total protein concentration in QEE treated groups. The expression level of IGF-1, FOXA-2, Stmn-2, SPP-1 was found significantly down-expressed. It is concluded that QEE treatment has the regenerative and hepatoprotective effect.

Farnesoid X Receptor Activation Impairs Liver Progenitor Cell-Mediated Liver Regeneration via the PTEN-PI3K-AKT-mTOR Axis in Zebrafish.

BACKGROUND AND AIMS: Following mild liver injury, pre-existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells (BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC-driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end-stage liver diseases. Despite this attention, the molecular basis of BEC-driven liver regeneration remains poorly understood. APPROACH AND RESULTS: By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC-driven liver regeneration. Here we show that FXR activation blocks the process through the FXR-PTEN (phosphatase and tensin homolog)-PI3K (phosphoinositide 3-kinase)-AKT-mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC-to-hepatocyte differentiation, but not BEC-to-LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena/b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC-driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K-AKT-mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC-driven liver regeneration, as did FXR activation. CONCLUSIONS: FXR activation impairs BEC-driven liver regeneration by enhancing PTEN activity; the PI3K-AKT-mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.

Hepatoprotective and antioxidant activities of Annona squamosa seed extract against alcohol-induced liver injury in Sprague Dawley rats.

Alcohol is regarded as the third most common cause of death after hypertension and smoking. Its long-term excess exposure leads to alcoholic liver disease (ALD) and liver injury, a worldwide health problem without efficient therapy. As there is no reliable liver protective drugs in allopathic medical practices, herbs play a major role in the management of liver diseases. Thus, the present study was designed to evaluate hepatoprotective activity of Annona squamosa seed extract against alcohol-induced liver injury in Sprague Dawley rats. Liver toxicity was induced by 50% alcohol at dose level of 12 ml/kg po each, for 8 days. Ethanolic extract of A. squamosa seed (EEAS) at dose of 200 and 400 mg/kg po were administered once daily for 8 consecutive days. The hepatoprotective activity of EEAS was assessed in experimental rats using various biochemical parameters like ALT, AST, ALP, LDH, SBL, albumin, total cholesterol, and total protein; and antioxidant parameters like SOD, CAT, GSH, and TBARS. It demonstrated that the treatment with EEAS significantly (p < 0.05-p < 0.001) and dose-dependently prevented the alcohol-induced increase in serum levels of hepatic enzymes and significantly increased the levels of SOD, CAT, and GSH. It also significantly decreased the level of MDA. Histopathology of the liver tissues showed that EEAS attenuated the hepatocellular necrosis and led to regeneration and repair of cells toward normal. Results of this study strongly indicated the protective effect of A. squamosa against alcohol-induced liver injury which may be attributed to its hepatoprotective and antioxidant activities.

Omega-3 polyunsaturated fatty acids prevent progression of liver fibrosis and promote liver regeneration after partial hepatectomy in cirrhotic rats.

OBJECTIVE: To assess the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on liver regeneration of rats with liver cirrhosis after hepatectomy and antifibrosis. MATERIALS AND METHODS: Omega-3 polyunsaturated fatty acids were intravenously injected in n-3 PUFA group 3 days before the operation to 1 day after partial hepatectomy. 70% hepatectomy was performed in rats, which were subsequently divided into 4 groups, namely normal and hepatectomy group (PH); liver cirrhosis and hepatectomy group (LC+PH); liver cirrhosis, n-3 PUFA (1 mL/kg), and hepatectomy group (LC+n-3 PUFA+PH); liver cirrhosis, n-3 PUFA (2 mL/kg) and hepatectomy group (LC+n-3PUFA*+PH). Body/liver weight ratios, serum parameters, histopathological examination, immunostaining, inflammatory cytokine and quantification of mRNA expression were also investigated. RESULTS: Liver regeneration was significantly delayed compared with PH group 7 days after hepatectomy (PH) in LC+PH group. Besides, liver regeneration of LC+n-3 PUFA*+PH group increased significantly compared with LC+PH group 7 days after PH. In LC+PH group, liver cirrhotic was significantly higher compared with LC+n-3 PUFA+PH group 7 days after PH. In the meantime, liver cirrhosis of LC+n-3 PUFA*+PH group was significantly reduced compared with LC+n-3 PUFA+PH group 7 days after PH. Anti-inflammatory cytokine IL-10 was increased and pro-inflammatory cytokine IL-6 was decreased in LC+n-3 PUFA*+PH group compared with LC+PH group. N-3 PUFA also suppressed increments in mRNA expression for transforming growth factor-ß and up-regulated the expression of matrix metalloproteinase-9 and matrix metalloproteinase-1 in the liver. CONCLUSIONS: The mentioned results clearly show that n-3 PUFA reduces liver fibrosis and promotes liver regeneration, even under cirrhotic conditions. This could be a potentially useful treatment for liver cirrhosis.

Pine ( Pinus densiflora ) needle extract could promote the expression of PCNA and Ki-67 after partial hepatectomy in rat.

PURPOSE: To investigate the effects of pine needle extract (PNE) on the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 during liver regeneration induced by 70% partial hepatectomy (PH) in rat. METHODS: Forty-eight male rats (SD, 7 weeks) had surgery (70% PH). They were randomly divided into two groups. PH + PNE group was only provided PNE diluted in water (10%) for drinking and PH group was provided water from 5 days before surgery to the time of sacrifice. PNE was made by pressing and filtering. Animals were sacrificed at 12h, 24h, 36h, 60h, 84h, 168h after PH, respectively. The expressions of PCNA and Ki-67 were determined as proliferation indices. RESULTS: Immunohistochemistry turned out to increase the expression of PCNA and Ki-67. PCNA expression of PH+PNE group increased up to twice of that of PH group. Western blot also seemed to increase the PCNA expression. These results indicated the promotion of cell proliferation in liver tissue and hepatic regeneration. CONCLUSIONS: Pine needle extract stimulates the expression of some mitotic proteins during liver regeneration induced by 70% PH in rats. It suggests that administration of pine needle extract could accelerate the liver regeneration after partial hepatectomy.

Panax notoginseng saponins promote liver regeneration through activation of the PI3K/AKT/mTOR cell proliferation pathway and upregulation of the AKT/Bad cell survival pathway in mice.

BACKGROUD: The regenerative capacity of the liver is crucial for the host to survive after serious hepatic injuries, tumor resection, or living donor liver transplantation. Panax notoginseng saponins (PNS) have been reported to exert protective effects during organ injuries. The present study aimed to evaluate the effect of PNS on liver regeneration(LR) and on injuries induced by partial hepatectomy (PH). METHODS: We performed 70% partial PH on C57BL/6 J mice treated with or without PNS. LR was estimated by liver weight/body weight, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and cell proliferation, and the related cellular signals were analyzed by Western blot. RESULTS: Different concentrations of PNS promoted hepatocyte proliferation in vitro. Mice in the PNS group showed higher liver/body weight ratios at 2 d and 7 d (P < 0.05) after PH and lower levels of serum ALT and AST (P < 0.05) compared to those of mice in the normal control (NC) group. Histological analysis showed that the expression of proliferating cell nuclear antigen(PCNA) at 2 d and 7 d after PH was significantly higher in the PNS group than in the NC group (P < 0.05). Mechanistically, the AKT/mTOR cell proliferation pathway and AKT/Bad cell survival pathway were activated by PNS, which accelerated hepatocyte proliferation and inhibited apoptosis (P < 0.05). CONCLUSIONS: PNS promoted liver regeneration through activation of PI3K/AKT/mTOR and upregulated the AKT/Bad cell pathways in mice.

Dihydromyricetin alleviates acetaminophen-induced liver injury via the regulation of transformation, lipid homeostasis, cell death and regeneration.

AIMS: We previously reported that Hovenia dulcis Thunb. extract, a traditional Chinese medicine rich in dihydromyricetin (DHM), exhibited a significant hepatoprotective effect against acetaminophen (APAP)-induced liver injury. However, whether DHM plays a protective role in APAP hepatotoxicity and what mechanisms are involved remain unclear. In this study, we evaluated the hepatoprotective effects of DHM against APAP-induced liver injury. MAIN METHODS: Male C57BL/6 mice were used for the experiment. LC-MS, q-PCR, immunochemistry and western blot analysis were employed to mechanism analysis. KEY FINDINGS: DHM exhibited a protective effect against APAP-induced liver injury. Further mechanistic investigations revealed that the protective effect of DHM against APAP hepatotoxicity had multi-target and multi-pathway characteristics involving APAP metabolism, lipid regulation, and hepatocyte death and regeneration. DHM pretreatment resulted in cytochrome P450 2E1 inhibition and UDP-glucuronosyltransferase 1A1 activation, affecting APAP biotransformation. Moreover, DHM pretreatment significantly ameliorated lipid dysregulation via peroxisome proliferator-activated receptor and sterol regulatory element-binding protein-1c (SREBP-1c) signalling pathways. Furthermore, DHM regulated the expression of cell death- and liver regeneration-associated proteins. SIGNIFICANCE: These results suggested that DHM alleviated APAP-induced liver injury in mice by inhibiting hepatocyte death, promoting p53-related regeneration, and regulating lipid homeostatic imbalance and APAP transformation. Based on these findings, DHM provides a potential and novel approach for preventing and treating APAP-induced liver damage, and SREBP-1c signalling might be a new therapeutic target for APAP hepatotoxicity.

Schisandra fruits for the management of drug-induced liver injury in China: A review.

BACKGROUND: With increasing use of pharmaceuticals, drug-induced liver injury (DILI) has become a significant therapeutic challenge to physicians all over the world. Drugs based on Schisandra fruits (SF for short, the fruits of Schisandra chinensis or Schisandra sphenanthera) or synthetic analogues of schisandrin C, are commonly prescribed for treating DILI in China. PURPOSE: This review summarizes the literature regarding the application of SF-derived drugs in patients with DILI and current understanding of mechanisms underlying the protective effects of SF against liver injury. METHODS: Keywords related to drug-induced liver injury and Schisandra fruits were searched in the following databases: Pubmed, Cochrane Library, Google Scholar, LiverTox, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal database (VIP), and Wanfang database. All studies, published in English or Chinese, were included. Clinical study exclusion criteria: if patients received other Chinese herbal medicines in a study, the study will not be included in this review. RESULTS: Clinical studies have shown that SF-derived drugs are effective in inhibiting drug-induced elevation of serum levels of alanine aminotransferase, aspartate transaminase and total bilirubin. Cellular and animal studies have demonstrated that crude SF extracts, lignan compounds found in SF, and SF-derived drugs are effective in protecting the liver against xenobiotic-induced injury. Regulation of cytochrome P450 enzyme activity, anti-oxidation, anti-inflammation and acceleration of liver regeneration are involved in the hepatoprotective mechanisms of SF. CONCLUSION: SF-derived drugs are effective in ameliorating DILI in China. To verify the clinical efficacy of these drugs, high-quality clinical studies are needed.

Nicotinamide induces liver regeneration and improves liver function by activating SIRT1.

Nicotinamide (Nam) has recently been characterized as an agent for tissue regeneration due to the observed pro­proliferation effects. However, the effect of Nam on liver regeneration remains undetermined. In the present study, the potency of Nam as a regimen to promote liver regeneration and restore liver function was evaluated following partial hepatectomy (PH) on C57BL/6 mice. Ki­67 immunohistochemical and cell cycle analyses demonstrated that exogenous Nam supplementation promoted the proliferation of hepatocytes and accelerated the recovery of liver tissue. The addition of Nam protected liver function following PH, as evidenced by hematoxylin and eosin staining of liver tissue morphology and measurement of serum liver injury markers. Notably, immunoblotting results revealed that the expression and activity of NAD­dependent protein deacetylase sirtuin­1 (SIRT1) were significantly upregulated following treatment with Nam, suggesting that Nam may promote liver regeneration through activation of SIRT1. The present study demonstrated that Nam regulated the process of liver regeneration and improved liver function by activating SIRT1, suggesting that Nam has the potency to be used for promoting liver regeneration following surgical resection.

Pine ( Pinus densiflora ) needle extract could promote the expression of PCNA and Ki-67 after partial hepatectomy in rat

Abstract Purpose To investigate the effects of pine needle extract (PNE) on the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 during liver regeneration induced by 70% partial hepatectomy (PH) in rat. Methods Forty-eight male rats (SD, 7 weeks) had surgery (70% PH). They were randomly divided into two groups. PH + PNE group was only provided PNE diluted in water (10%) for drinking and PH group was provided water from 5 days before surgery to the time of sacrifice. PNE was made by pressing and filtering. Animals were sacrificed at 12h, 24h, 36h, 60h, 84h, 168h after PH, respectively. The expressions of PCNA and Ki-67 were determined as proliferation indices. Results Immunohistochemistry turned out to increase the expression of PCNA and Ki-67. PCNA expression of PH+PNE group increased up to twice of that of PH group. Western blot also seemed to increase the PCNA expression. These results indicated the promotion of cell proliferation in liver tissue and hepatic regeneration. Conclusions Pine needle extract stimulates the expression of some mitotic proteins during liver regeneration induced by 70% PH in rats. It suggests that administration of pine needle extract could accelerate the liver regeneration after partial hepatectomy.

Loss of trefoil factor 1 inhibits biliary regeneration but accelerates the hepatic differentiation of progenitor cells in mice.

Although the regeneration of the adult liver depends on hepatic progenitor cells (HPCs), many uncertainties regarding hepatic regeneration in the injured liver remain. Trefoil factor family 1 (TFF1), a secretory protein predominantly expressed in the gastrointestinal tract, is responsible for mucosal restitution. Here, we investigated the role of TFF1 in liver regeneration using a mouse model of hepatic injury (choline-deficient ethionine-supplemented diet and carbon tetrachloride administration) and genetically engineered mice (TFF1 knockout (TFF1-/-)). Immunohistochemistry analysis of human liver samples revealed TFF1 expression in the hepatocytes close to ductular reaction and the regenerating biliary epithelium in injured liver. The number of cytokeratin 19 (CK19)-positive bile ducts was significantly decreased in the TFF1-/- mice after liver injury. Notch pathway in the TFF1-/- mice was also downregulated. HPCs in the control mice differentiated into biliary cells (CK19+/SRY HMG box 9 (SOX9)+) more frequently. In contrast, HPCs in the TFF1-/- mice more frequently differentiated into a hepatic lineage (alpha fetoprotein+/SOX9+) after acute liver damage. Hepatocyte proliferation was upregulated, and the liver weight was increased in TFF1-/- mice in response to chronic liver damage. Thus, TFF1 is responsible for liver regeneration after liver injury by promoting HPC differentiation into a biliary lineage and inhibiting HPC differentiation into a hepatic lineage.

Salicornia ramosissima J. Woods seeds affected the normal regenerative function on carbon tetrachloride-induced liver and kidney injury.

The growing importance of Salicornia plants as bioactive agents and health promoters associated with the continuous demand for alternative treatments for liver disorders, has stimulated us to evaluate the renal and hepatic effects of S. ramosissima seeds in mice under normal conditions and exposure to toxic products as carbon tetrachloride (CCl4). Thus, histopathological and lipid peroxidation evaluations of the liver and kidneys were performed. Powdered dried seeds of S. ramosissima (SRS) were administered orally for 22 days at a dose of 2000 mg/kg/day to male mice in three different settings: 1) seed effects, 2) protection against CCl4 acute toxicity (0.2 mL/kg) and 3) regeneration after acute exposure to CCl4 (0.2 mL/kg), each study being performed with appropriate control animals. Mice treated with SRS per se had slightly enlarged hepatic sinusoids and noticeable renal inflammation. SRS did not show effective protection against mice exposed to CCl4 and had no positive influence on liver and kidney recovery after CCl4 administration. These results demonstrated that SRS failed to improve hepato- and nephrotoxicity, in addition to the apparent synergism between CCl4 and SRS under these experimental conditions. Although the biological mechanisms of S. ramosissima are not fully understood, the evidence suggests further research to elucidate its adverse biological effects.

Capsiate treatment in liver surgeries may compromise its recovery.

PURPOSE: To investigate the effects of capsiate treatment on hepatic hyperplasia in partially hepatectomized rats. METHODS: The animals were divided into a Capsiate group (CPH), a Capsiate Post-Partial Hepatectomy group (CPPH) and a Partial Hepatectomy Control group (PH). CPH and CPPH animals received 60 mg/kg/day Capsiate for 30 days. Next, the rats underwent partial hepatectomy. CPPH animals continued to receive treatment for 48 h after partial hepatectomy. Liver tissue and intracardiac blood samples were obtained 24 or 48 h after PH. RESULTS: Capsiate treatment interfered with hepatic parameters, reducing the number of mitoses and apoptosis and increasing blood ALT and alkaline phosphatase concentrations. CONCLUSION: Capsiate treatment preceding hepatic surgery may compromise the initial period of postoperative recovery.

Capsiate treatment in liver surgeries may compromise its recovery

Abstract Purpose: To investigate the effects of capsiate treatment on hepatic hyperplasia in partially hepatectomized rats. Methods: The animals were divided into a Capsiate group (CPH), a Capsiate Post-Partial Hepatectomy group (CPPH) and a Partial Hepatectomy Control group (PH). CPH and CPPH animals received 60 mg/kg/day Capsiate for 30 days. Next, the rats underwent partial hepatectomy. CPPH animals continued to receive treatment for 48 h after partial hepatectomy. Liver tissue and intracardiac blood samples were obtained 24 or 48 h after PH. Results: Capsiate treatment interfered with hepatic parameters, reducing the number of mitoses and apoptosis and increasing blood ALT and alkaline phosphatase concentrations. Conclusion: Capsiate treatment preceding hepatic surgery may compromise the initial period of postoperative recovery.

Administration of Ginkgo biloba Extract (EGb761) Alone and in Combination with FK506 Promotes Liver Regeneration in a Rat Model of Partial Hepatectomy.

BACKGROUND: Free radical damage is known to occur during liver regeneration. The Ginkgo biloba extract EGb761 has antioxidant properties due to its ability to scavenge free radicals. FK506 has been widely used as an immunosuppressant that stimulates hepatocyte proliferation following partial hepatectomy. AIMS: To explore whether EGb761 enhances liver regeneration after hepatectomy in rats, we investigated the effects of EGb761 alone and in combination with FK506 on the liver regenerative process. STUDY DESIGN: Animal experimentation. METHODS: A total of 75 Wistar albino rats weighing 340.08±11.66 g were randomly divided into five experimental groups: sham, control, FK506, EGb761, and FK506 + EGb761. According to the study groups, rats were administered FK506 at a dose of 0.1 mg/kg/day and EGb761 at 25 mg/kg/day three times via the intraperitoneal route. Then, two-thirds hepatectomy was performed according to the Higgins and Anderson technique in all the rats. At postoperative 48 h, 53 surviving rats were sacrificed. Serum and plasma samples were collected for analyzing thymidine kinase and oxidative stress marker levels. The regenerated liver was entirely resected, weighed, and sectioned. The mitotic index was assessed using hematoxylin-eosin staining. The extent of liver regeneration was calculated using the Child's formula. The data were statistically analyzed using ANOVA, with a significance level of 5% (p<0.05). RESULTS: Rats who received EGb761 showed significantly higher levels of liver regeneration than those who received FK506 or FK506 + EGb761 (p<0.01). Thymidine kinase level and mitotic index were significantly higher in the EGb761 (p<0.005) and FK506 (p<0.05) groups than in the control and sham groups. In addition, the liver regeneration percentage was significantly higher in the EGb761 group than in the FK506 group (p<0.01). Myeloperoxidase and malondialdehyde levels were significantly correlated between the EGb761 and FK506 groups, even at lower levels in the EGb761 group (p<0.001). CONCLUSION: EGb761, which is an antioxidant, reduces liver damage and stimulates liver regeneration following partial hepatectomy in rats through its anti-inflammatory and antioxidative effects.

Hepatic Regeneration and Reno-Protection by Fish oil, Nigella sativa Oil and Combined Fish Oil/Nigella sativa Volatiles in CCl4 Treated Rats.

The aim of the present research was to investigate the effect of fish oil, crude Nigella sative oil and combined fish oil/Nigella sative volatile oil as hepato-regenerative and renal protective supplements. The oils were administered as emulsions to rat model with liver injury induced by CCl4. Plasma activities of transaminases (AST and ALT) were evaluated as liver function indicators, while plasma creatinine and urea and creatinine clearance were determined as markers of kidney function. Plasma malondialdehyde (MDA), nitrite (NO) and tumor necrosis factor-α (TNF-α) were estimated to assess the exposure to oxidative stress and subsequent inflammation. Liver fat was extracted and their fatty acids´ methyl esters were determined using gas chromatography. Results showed that plasma activities of AST and ALT were significantly higher in CCl4 control group compared to control healthy group. Plasma levels of creatinine and urea increased significantly in CCl4 control, while creatinine clearance was reduced significantly in the same group. All rat treated groups given the three oil emulsions showed improvement in liver function pointing to the initiation of liver regeneration. The combination of fish oil/Nigella sative volatiles showed the most promising regenerative activity. Oxidative stress and inflammation which were increased significantly in CCl4 control group showed improvement on administration of the three different oil emulsions. Fatty acids methyl ester of liver fat revealed that rats treated with fish oil/Nigella sative volatile oil presented the highest content of unsaturated fatty acids (45.52% ± 0.81) while fish oil showed the highest saturated fatty acids (53.28% ± 1.68). Conclusion; Oral administration of oil emulsions of native fish oil, Nigella sative crude oil and combined fish oil/Nigella sative volatile oil reduced liver and kidney injury in rat model of CCl4 through exerting anti-inflammatory and antioxidant activity. Fish oil/Nigella sative volatile oil emulsion was the most promising hepato-regenerative and reno-protective formula among the different groups.

Effect of dioscin on promoting liver regeneration via activating Notch1/Jagged1 signal pathway.

BACKGROUND: Development of novel candidates to promote liver regeneration is critical important after partial hepatectomy (PH). Dioscin, a natural product, shows potent effect on liver protection in our previous works. PURPOSE: This work aimed to investigate the effect and underlying mechanisms of dioscin on liver regeneration. METHODS: The promoting proliferation effects of dioscin on mouse hepatocytem AML12 cells, rat primary hepatocytes, rats and mice after 70% PH were evaluated. RESULTS: Dioscin significantly promoted proliferation of rat primary hepatocytes and AML12 cells through MTT, BrdU and PCNA staining assays. Meanwhile, dioscin rapidly recovered the liver to body weight ratios, declined ALT and AST levels, and relieved hepatocytes necrosis compared with 70% PH operation groups in rats and mice. Mechanistic test showed that dioscin significantly increased Notch1 and Jagged1 levels, and accelerated γ-secretase activity by up-regulating PS1 expression, leading to nuclear translocation of Notch1 intracellular domain (NICD1). Subsequently, the significant activation of Notch-dependent target genes (Hey1, Hes1, EGFR, VEGF), and cell-cycle regulatory proteins (CyclinD1, CyclinE1, CDK4 and CDK2) were all recognized. In addition, these results were further confirmed by Notch1 siRNA silencing and inhibition of γ-secretase by DAPT (a well-characterized γ-secretase inhibitor) in vitro. CONCLUSIONS: Dioscin, as a novel efficient γ-secretase activator, NICD1 nucleus translocation promoter and cell cycle regulator, markedly activated Notch1/Jagged1 pathway to promote hepato-proliferation. Our findings provide novel insights into dioscin as a natural product with facilitating liver regeneration after PH.

Perioperative oral supplementation with fish oil promotes liver regeneration following partial hepatectomy in mice via AMPK activation.

The present study aimed to observe the effects of perioperative oral supplementation with fish oil (FO) on liver regeneration in mice and examine the potential mechanism. A total of 120 male ICR mice were randomly divided into 5 groups: Sham, Control, fish oil (FO), Compound C [the AMP­activated protein kinase (AMPK) inhibitor dorsomorphin], and Compound C + FO. Changes in liver function, alterations in hepatocyte proliferation and in the expression of polarization markers, and activation of AMPK signaling were examined following partial hepatectomy (PH). The results demonstrated that restoration of serum alanine aminotransferase (ALT) and total bilirubin (TBIL) levels were significantly faster in FO­treated mice compared with Control mice, and this effect was suppressed by treatment with Compound C. FO­treated mice exhibited increased numbers of Ki­67 positive hepatocytes and their postoperative liver­to­body weight ratio was significantly increased compared with the Control mice, which was also suppressed by co­treatment with the AMPK inhibitor. Furthermore, protein expression of Occludin, Claudin­3, tight junction protein 1 and bile salt export pump was gradually increased in FO­treated mice compared with Control, whereas Compound C treatment reversed this effect. Therefore, the present study revealed that perioperative oral supplementation with FO may promote liver regeneration and improved liver function in mice following PH through AMPK activation.